Structure-function analysis for the induction of pathogenic signaling by H. pylori CagA oncoprotein

• Project/Area Number: 18K07105
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49050:Bacteriology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hayashi Takeru 東京大学, 大学院医学系研究科(医学部), 助教 (10722209)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 胃がん / ピロリ菌 / CagA / 新規創薬 / 胃発がん

Outline of Final Research Achievements

Helicobacter pylori CagA oncoprotein is closely associated with gastric carcinogenesis. In this study, I succeeded in reconstitution of the complex formation of CagA with multiple human proteins. CagA-SHP2 complex formation was promoted by CagA-PAR1b interaction and, in contrast, suppressed by CagA-Csk interaction, which required homo-dimerization of Csk. Thus, a series of analyses revealed that the CagA interacts with multiple proteins in a more complicated manner than expected. Furthermore, I found small compounds with novel chemical structures that selectively inhibit SHP2 oncoprotein, which is aberrantly activated by CagA.

Academic Significance and Societal Importance of the Research Achievements

ピロリ菌CagAは胃がんに深く関わり、CagAによるヒトタンパク質の脱制御がその病原活性の本態と考えられる。本研究の解析により、CagAが細胞内のPAR1b、SHP2ならびにCskと形成するシグナル撹乱複合体の生化学的性質が新たに明らかになった。また、がんタンパク質として明確な位置づけにあるSHP2は、依然としてその機能に不明な点が多いものの近年創薬の標的としても大きな注目を浴びている。本研究ではSHP2の新たな機能を明らかにするとともに、新規創薬への展開が期待できる結果を得た。

Research Products

• [Journal Article] Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1 (2020)
  • Author(s): Chi Ben, Xiaojing Wu, Atsushi Takahashi-Kanemitsu, Christopher Takaya Knight, Takeru Hayashi, Masanori Hatakeyama
  • Journal Title: The Journal of Biological Chemistry Volume: 295 Issue: 41 Pages: 13965-13980
  • DOI: 10.1074/jbc.ra120.013820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ピロリ菌の遺伝子多型と胃がん発症リスクを結びつける分子構造解析 (2019)
  • Author(s): 林剛瑠
  • Journal Title: 日本ペプチド学会ニュースレター Volume: 112 Pages: 5-9
  • Open Access
• [Journal Article] Evaluating the origin and virulence of a Helicobacter pylori cagApositive strain isolated from a non-human primate (2018)
  • Author(s): Kana Hashi, Chihiro Imai, Koji Yahara, Kamrunnesa Tahmina, Takeru Hayashi, Takeshi Azuma, Takako Miyabe-Nishiwaki, Hideyuki Sato, Masao Matsuoka, Sachi Niimi, Munehiro Okamoto, Masanori Hatakeyama
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15981-15981
  • DOI: 10.1038/s41598-018-34425-4
  • NAID: 120006539613
  • Peer Reviewed / Open Access
• [Presentation] Structure-function analysis for deregulation of SHP2 by geographically distinct variants of Helicobacter pylori CagA (2018)
  • Author(s): Takeru Hayashi, Miki Senda, Nobuhiro Suzuki, Chi Ben, Toshiya Senda, Masanori Hatakeyama
  • Organizer: The 37th Sapporo International Cancer Symposium
  • Int'l Joint Research
• [Book] Photon Factory Highlights 2017 (2018)
  • Author(s): Takeru Hayashi, Miki Senda, Nobuhiro Suzuki, Toshiya Senda, Masanori Hatakeyama
  • Total Pages: 2
  • Publisher: High Energy Accelerator Research Organization (KEK)
• [Remarks] 1つのアミノ酸の違いが日本人胃がん多発の背景に -ピロリ菌の発がん活性を規定する分子構造基盤-
  • URL: https://www.u-tokyo.ac.jp/focus/ja/articles/a_00617.html